Compositions and methods for treating eye diseases

ABSTRACT

A method for treating an eye disease of an affected eye includes administering to the affected eye of a subject in need of such treatment a steroidal-androgen-free composition containing a therapeutically effective amount of beta-cyclodextrin derivative. The eye disease can be meibomian gland dysfunction, blepharitis, or dry eye disease. A steroidal-androgen-free composition includes a beta-cyclodextrin derivative as a sole active pharmaceutical ingredient. The steroidal-androgen-free composition is an ophthalmic composition.

The present invention claims priority to U.S. Provisional ApplicationNo. 62/869,133, filed on Jul. 1, 2019, and 62/903,898, filed on Sep. 22,2019, both of which are incorporated by reference for all purposes as iffully set forth herein.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for treatingmeibomian gland dysfunction (MGD), blepharitis, dry eye disease andrelated ocular indications of an affected eye. The invention alsorelates to compositions for artificial tears or eye lubricants.

BACKGROUND OF THE INVENTION

Meibomian glands are a type of sebaceous gland located in the tarsalplate of the upper and lower eyelids. These glands are responsible forthe supply of meibum, an oily substance that prevents evaporation of theeye's tear film, prevents tear evaporation, and makes the closed lidsairtight. There are approximately 50 glands on the upper eyelids and 25glands on the lower eyelids. Meibomian glands are distinguished bygrape-like clusters of acini on the mucocutaneous lid junction and emptytheir lipid content (meibum) at this junction in order to coat theocular surface via holocrine secretion. The glands are anchored by cellsthat produce both polar and nonpolar lipids, which are then stored inlysosomes that merge into larger storage granules. As these cellscontinue to enlarge with lipid, they eventually commit apoptosis andrupture to release the meibum into the meibomian gland opening and spillthe meibum over the ocular surface. Meibum is fluid at the temperatureof ocular surface, and distributed over the ocular surface in a thin,smooth film on top of the aqueous layer. This lipid layer preventsevaporation of the aqueous layer. Alterations in the meibum composition,property and level can have a profound effect on the health of theeyelid margins and ocular surface. Meibomian gland dysfunction in thegeneral population is pretty high with some estimates as high as 39%with an increase in incidence in contact lens wearers.

Meibomian gland secretions form the lipid layer of tears and consist ofpolar and nonpolar lipids. The lipid composition of the meibum canaffect tear parameters like initial formation of a composite monolayerwith polar and nonpolar phases, adequate fluidity near body temperature,and the ability to undergo compression and expansion during blinking.These properties are very important for effective polar lipidstructuring and fluidity (melted physical state) at normal bodytemperature. Any alterations in the saturation of the fatty acids canlead to instability of tears.

MGD patients usually have normal production of aqueous tears by theirlacrimal glands, their meibomian glands can atrophy and this isfrequently accompanied by metaplasia of the ductal epithelium of theseglands. Anterior erosion of the mucocutaneous junction of the eyelid isoften noted, as well as eyelid and conjunctival infection, eyelid marginirregularity, corneal epithelial changes, and corneal vascularization.In some cases, abnormal overproduction of meibum can also cause the sameproblems.

As meibomian glands lining the eyelids produce lipids that promote thestability of the tears and reduce evaporation of the tear film,dysfunction of the meibomian glands can lead to lipid insufficiency thatdestabilizes the tear film and causes decreases in tear film break-uptime and evaporative dry eye.

MGD may also be characterized by increased melting point of the lipids,causing solidification of the lipids and obstruction of the meibomiangland secretion. This can result in cysts, infections and decreasedlipid content in the tears. MGD is also characterized by excess,abnormally turbid secretion that gets inspissated and plugs themeibomian orifices. This is followed by metaplasia of the meibomianducts (abnormal hyper-keratinization). Blockage and resistance to flowresults in inflammation and vascularization (redness) of tissues aroundthe orifice. Inflammatory mediators accumulate in the tear film leadingto damage of ocular surface. Sequalae of all these events isinflammatory scarring of the duct leading to stenosis. Initially glandsswell and eventually atrophy.

Common complaints of MGD patients include blurred or filmy vision, lightsensitivity or photophobia, burning or foreign body sensations in theeye, excessive tearing, intolerance to contact lens and pain.

Light sensitivity is an intolerance of sunlight, fluorescent light orincandescent light. It is one of the symptoms of MGD and is associatedwith other conditions such as corneal abrasion, uveitis, meningitis, adetached retina, contact lens irritations, sunburn or refractivesurgery.

Blurred vision is a lack of sharpness of vision, and may result fromabnormalities such as nearsightedness, farsightedness, presbyopia, andastigmatism. It is also associated with MGD and other ocular surfaceconditions.

Currently, various lipid based artificial tears or lubricants are usedto alleviate the symptoms of MGD. Physical treatments, such asmaintaining good hygiene, heating, and massage, are often used as well.However, these treatments do not cure the disease. There is a need foran effective and safe treatment for MGD.

Among MGD patients, blepharitis and dry eye disease are frequent as adirect or indirect result of MGD. These conditions share many of thesame symptoms discussed above and are considered as indications relatedto MGD. Both these conditions are very complicated with multifactorialcauses. They are briefly described in the following sections.

Blepharitis is inflammation of the eyelids that usually affects botheyes along the edges of the eyelids. It is a condition that can developat later stages of MGD or independent of MGD. MGD causes posteriorblepharitis when meibomian glands are clogged and engorged. Commonly,this is associated with acne rosacea, and hormonal causes are suspected.Anterior blepharitis is caused by bacterial infections and can betreated with antibiotics. Both anterior and posterior blepharitis may becaused by a Demodex mite. The exact pathophysiology of blepharitis ismultifactorial and is still not very clear. Patients with blepharitisoften have symptoms observed in MGD and dry eye disease, includingitching, burning, and crusting of the eyelids. They may also experiencetearing, blurred vision and foreign body sensation.

Dry eye disease (DED) is a condition in which a person doesn't haveenough quality tears to lubricate and nourish the eye. Tears arenecessary for maintaining the health of the front surface of the eye andfor providing clear vision. Dry eye is a common and often chronicproblem. The prevalence worldwide is estimated from 5% to 34%.Inadequate amount or quality of tear is the cause of DED. Tearproduction diminishes with age, with various medical conditions or as aside effect of certain medicines. Environmental conditions, such as windand dry climates, can also decrease tear volume due to increased tearevaporation. When the normal amount of tear production decreases ortears evaporate too quickly from the eyes due to abnormal meibum lipid,symptoms of dry eye disease can develop. The DED mainly caused byreduced tear production is defined as aqueous-deficient DED. The DEDcaused by increased tear evaporation is defined as evaporative DED. Thelatter is the majority, but many patients have mixed causes.

Most of the current DED treatment aim to attenuate the immune responses.This invention focuses on the improvement tear film stability to attackone of the early pathological events of the disease.

SUMMARY OF THE INVENTION

In one embodiment, a method for treating an eye disease of an affectedeye includes administering to the affected eye of a subject in need ofsuch treatment a steroidal-androgen-free composition containing atherapeutically effective amount of beta-cyclodextrin derivative. Thebeta-cyclodextrin derivative is an active pharmaceutical ingredient fortreating the eye disease, and the beta-cyclodextrin derivative is a soleactive pharmaceutical ingredient for treating the eye disease.

In another embodiment, the eye disease is one selected from the groupconsisting of a meibomian gland dysfunction, a blepharitis, and a dryeye disease.

In another embodiment, the steroidal-androgen-free composition isadministered topically to the affected eye or topically onto asurrounding skin of the affected eye.

In another embodiment, the beta-cyclodextrin derivative is selected fromthe group consisting of (2-hydroxypropyl)-beta-cyclodextrin,methyl-beta-cyclodextrin, 6-monodeoxy-6-monoazido-beta-cyclodextrin,6-monodeoxy-6-monoiodo-beta-cyclodextrin,6-monodeoxy-6-monothio-beta-cyclodextrin,6-monodeoxy-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monobromo-beta-cyclodextrin,heptakis(2,3,6-tri-O-benzoyl)-beta-cyclodextrin,heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin,heptakis(2,6-di-O-methyl)-beta-cyclodextrin,heptakis(6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-chloro)-beta-cyclodextrin,heptakis(6-deoxy-6-bromo)-beta-cyclodextrin,heptakis(6-deoxy-6-iodo)-beta-cyclodextrin,heptakis(6-deoxy-6-thio)-beta-cyclodextrin, sulfobutylatedbeta-cyclodextrin, acetyl beta-cyclodextrin,carboxymethyl-beta-cyclodextrin, succinyl-beta-cyclodextrin,(2-carboxyethyl)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin,6-monodeoxy-6-monoamino-beta-cyclodextrin,heptakis(6-deoxy-6-amino)-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(2,3,-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoaminoto -beta-cyclodextrin,6-monodeoxy-6-monoamino-random-methyl-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(6-sulfo)-beta-cyclodextrin, heptakis (2,3-di-O-acetyl-6-sulfo)beta cyclodextrin, heptaki s(2,3 -di-O-methyl-6-sul fo)-b eta-cy cl °dextrin, heptaki s(2,3 -di-O-methyl-6-deoxy-6-amino)-beta-cyclodextrin,heptaki s(2,3-di-O-methyl-6-deoxy-6-azido)-beta-cyclodextrin, heptakis(6-deoxy-6-(2-carboxyethyl)thio)-beta-cyclodextrin, and a combinationthereof.

In another embodiment, the beta-cyclodextrin derivative is present inthe composition at a concentration of 0.1% w/w to 30% w/w, 0.5% w/w to25% w/w, 1% w/w to 20% w/w, 5% w/w to 15% w/w, 8% w/w to 12% w/w, about10% w/w, or 10% w/w.

In another embodiment, the steroidal-androgen-free composition does notinclude an androgen with a steroidal chemical structure, testosterone,or precursors of testosterone.

In another embodiment, the method further includes maintaining effectsof treating the meibomian gland dysfunction for a period of time postadministering.

In another embodiment, the period of time post administering is 1 month,2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months or 12 months.

In another embodiment, the method further includes dissolving lipidscrystals deposited at the opening of the meibomian gland of the affectedeye; and increasing tear film stability.

In another embodiment, the method further includes one selected from thegroup consisting of: reducing the sensation of a foreign body in theaffected eye, hyperemia or redness of the affected eye and eyelidmargin, plugging of a meibomian gland orifice of the affected eye,inflammation of ocular tissues, corneal staining of the affected eye,burning sensation in the affected eye, photophobia, blurred vision, painin the affected eye, or itchiness in the affected eye; increasing tearfilm break up time (TBUT); improving astigmatism; decreasing the phasetransition temperature of meibum; improving clinical signs and symptomsof meibomian gland dysfunction (MGD); and a combination thereof. Theocular tissues are selected from the group consisting of meibomianglands, ducts, orifices, eye lids, cornea, and conjunctiva.

In another embodiment, a steroidal-androgen-free composition includes abeta-cyclodextrin derivative as a sole active pharmaceutical ingredient.The steroidal-androgen-free composition is an ophthalmic composition.

In another embodiment, the steroidal-androgen-free composition consistsessentially of the beta-cyclodextrin derivative and one or moreingredients selected from the group consisting of hydroxypropyl guar,xantham gum, trehalose, sodium chloride, castor oil, cremophor ELP,Polysorbate 80, HPMC 2910, edetate disodium, glycerin, a buffer agent,and water.

In another embodiment, the buffer agent is selected from the groupconsisting of sodium phosphate monobasic monohydrate, citric acid, andsodium citrate.

In another embodiment, the beta-cyclodextrin derivative is present inthe steroidal-androgen-free composition at a concentration of 0.1% w/wto 30% w/w.

In another embodiment, in this steroidal-androgen-free composition, thebeta-cyclodextrin derivative is selected from the group describe above.

In another embodiment, the steroidal-androgen-free composition is asolution, a suspension, an emulsion, a gel, an ointment, or a cream.

In another embodiment, the steroidal-androgen-free composition is anartificial tear or a lubricant.

In another embodiment, a steroidal-androgen-free composition consists ofa beta-cyclodextrin derivative, sodium chloride, a buffer agent, andwater.

In another embodiment, in this steroidal-androgen-free composition, thebeta-cyclodextrin derivative is selected from the group describe above.

In another embodiment, the buffer agent is selected from the groupconsisting of sodium phosphate monobasic monohydrate, citric acid, andsodium citrate.

In another embodiment, the steroidal-androgen-free composition consistsof 5%-20% of the beta-cyclodextrin derivative, 0.20%-0.80% of sodiumchloride, 0.10-0.30% of sodium phosphate monobasic monohydrate, andwater.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a furtherunderstanding of the invention and are incorporated in and constitute apart of this specification, illustrate embodiments of the invention andtogether with the description serve to explain the principles of theinvention.

In the drawings:

FIG. 1 shows the effects of 2-hydroxypropyl-beta-cyclodextrin(2-HP-β-CD) on sensitivity to light and blurred vision over a 24-weekperiod in a Phase 2 clinical trial.

FIG. 2 shows the effects of 2-HP-β-CD on sensitivity to light andblurred vision over a 12-month period in a Phase 2 clinical trial.

FIG. 3 shows the overall average score of patients treated in thedisease eye with a topical ocular drop of2-hydropropyl-beta-cyclodextrin formulation at a concentration of 10%(w/w), 3 times daily for 4 weeks with subsequent continuous observationsfor 5 months in a Phase 2 clinical trial.

FIG. 4 shows the average ocular symptom score of the patients in a Phase2 clinical trial.

FIG. 5 shows the average vision-related functioning score in a Phase 2clinical trial.

FIG. 6 shows the average quality of life impact score of the patients ina Phase 2 clinical trial.

FIG. 7 shows ocular symptom score at each schedule visit for pterygiumpatients with dry eye or with no dry eye in a Phase 2 clinical trial.

FIG. 8 shows average change from baseline of ocular symptom score ateach schedule visit for pterygium patients with dry eye or with no dryeye in a Phase 2 clinical trial.

FIG. 9 shows ocular symptom score at each schedule visit for pterygiumpatients with dry eye in a Phase 2 clinical trial.

FIG. 10 shows average change from baseline of ocular symptom score ateach schedule visit for pterygium patients with dry eye in a Phase 2clinical trial.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS

Reference will now be made in detail to embodiments of the presentinvention, example of which is illustrated in the accompanying drawings.

The present invention provides compositions and treatment methods fortreating meibomian gland dysfunction (MGD), blepharitis and dry eyedisease. Without being bound by a particular theory, the methods utilizetwo important properties of the cyclodextrin derivatives: 1) the abilityto sequester and dissolve cholesterol and 2) the ability to inhibitimmune activities such as macrophage activation. The first ability willhelp to remove excess lipids deposited near the orifice of meibomiangland and help the flow of lipid and it will also modify the meibumcomposition to make it more fluid at the normal temperature of theocular surface. The second ability will attenuate the abnormal immuneactivity present on the eyes of MGD patients. These patients sufferincreased cytokines and immune cell activities, including macrophages,T-cells. Unlike the current treatments for MGD, this invention will havethe potential to modify the disease in addition to improve symptoms suchas light sensitivity and blurred vision.

Cyclodextrins belong to the family of cyclic oligosaccharides,consisting of a macrocyclic ring of glucose subunits joined bya-1,4-glycosidic bonds. Cyclodextrins may contain a number of glucosemonomers ranging from six to eight units in a ring, creating a coneshaped molecule. Natural cyclodextrins include alpha-, beta- andgamma-cyclodextrins, corresponding to 6, 7, and 8 glucose units,respectively. The number of the glucose units is important forbiological and non-biological activities associated with thesemolecules. This application discloses surprise findings on cholesterolbinding abilities in relation to the number of glucose units. Theinventors of the present application discovered that the 7-unitbeta-cyclodextrins, but not the 6- and 8-unit alpha- andgamma-cyclodextrins, can have significant binding of cholesterol.

Natural cyclodextrins can be chemically modified by additions of othergroups, e.g., hydroxypropyl, methyl groups, to create “cyclodextrinderivatives.” The cyclodextrin derivatives can have different physicaland chemical properties and behave differently when interacting withother molecules. This discloses a surprise finding on how differentmodifications groups in cyclodextrin derivatives determine the abilitiesof cyclodextrin derivatives to dissolve cholesterol in water. The methylderivatives of beta-cyclodextrin have the best ability to dissolvecholesterol in water, followed by hydroxypropyl derivatives. Asdiscussed below, the rank order findings of various cyclodextrinderivatives will support the composition and method application.

The disclosure is based on the surprise finding by the inventors thatonly certain derivatives of the beta type of cyclodextrin have thesignificant ability to sequester and dissolve cholesterol. Anothersurprise finding is that certain modifications of the beta-cyclodextrinis more effective than others in cholesterol sequestration. Thesesurprise findings are the basis of the disclosure wherein selectedderivatives of a selected cyclodextrin is used as compositions andmethods for treating MGD, blepharitis and dry eye disease. Specifically,beta-cyclodextrin derivatives used herein can be(2-hydroxypropyl)-beta-cyclodextrin, methyl-beta-cyclodextrin,6-monodeoxy-6-monoazido-beta-cyclodextrin,6-monodeoxy-6-monoiodo-beta-cyclodextrin,6-monodeoxy-6-monothio-beta-cyclodextrin,6-monodeoxy-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monoazido-6-mono-0-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monobromo-beta-cyclodextrin,heptakis(2,3,6-tri-O-benzoyl)-beta-cyclodextrin,heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin,heptakis(2,6-di-O-methyl)-beta-cyclodextrin,heptakis(6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-chloro)-beta-cyclodextrin,heptakis(6-deoxy-6-bromo)-beta-cyclodextrin,heptakis(6-deoxy-6-iodo)-beta-cyclodextrin,heptakis(6-deoxy-6-thio)-beta-cyclodextrin, sulfobutylatedbeta-cyclodextrin, acetyl beta-cyclodextrin,Carboxymethyl-beta-cyclodextrin, Succinyl-beta-cyclodextrin,(2-carboxyethyl)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin,6-monodeoxy-6-monoamino-beta-cyclodextrin, heptakis(6-deoxy-6-amino)beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(2,3,-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoamino-beta-cyclodextrin,6-monodeoxy-6-monoamino-random-methyl-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl beta-cyclodextrin,heptakis(6-sulfo)-beta-cyclodextrin, heptakis (2,3-Di-O-acetyl-6-sulfo)beta cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo) beta cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-amino) beta cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-azido) beta-cyclodextrin,heptakis(6-deoxy-6-(2-carboxyethyl)thio) beta-cyclodextrin or acombination thereof.

U.S. Pat. No. 9,937,188 (Allergan, Inc) discloses the use offormulations comprising testosterone or related androgens for thetreatment of keratoconjunctivitis sicca and meibomian gland disease. Inthis patent, cyclodextrin acts as a solubilizer for testosterone, theactive ingredient, and is disclosed as one of the inactive excipientsthat also include castor oil, C10-30 alkyl acrylate crosspolymer andPolyoxyl 40 stearate. The methods of the present application arefundamentally different in two respect: 1) certain derivatives ofcyclodextrin, not cyclodextrin in general is disclosed here for thecompositions and methods; 2) the disclosed compounds are used as theactive ingredient for the treatment of MGD and related disease, not asan inactive excipient of a formulation as disclosed in U.S. Pat. No.9,937,188. Importantly, the disclosed method does not use any steroidalandrogen as disclosed in U.S. Pat. No. 9,937,188. This key differencewill avoid many of the potential steroidal-related side effects, such asvirilization for females and stimulation of the prostate for males.Androgens control the development, differentiation, and function of malereproductive and accessory sex tissues. Testosterone regulates theexpression of thousands of genes in ocular tissues. Such generegulations in meibomian gland provides the beneficial effects disclosedin U.S. Pat. No. 9,937,188, but since a very large number of genes'expression are changed, side effect potential is also high. ANDROGEL,containing 1% testosterone as an active ingredient, was approved fortopical use as a replacement therapy in males for conditions associatedwith a deficiency or absence of endogenous testosterone. ANDROGELproduct insert indicates the worsening of benign prostatic hyperplasia(BPH) and potential risk of prostate cancer for patients with BPH.ANDROGEL 1% should be avoided for unintentional exposure to women orchildren. Secondary exposure to testosterone can produce signs ofvirilization and ANDROGEL 1% should be discontinued until the cause ofvirilization is identified. Other observed side effects in the clinicaltrials of ANDROGEL 1% included azoospermia, edema with or withoutcongestive heart failure, sleep apnea. Serum testosterone, prostatespecific antigen, hemoglobin, hematocrit, liver function tests and lipidconcentrations should be monitored periodically for patients treatedwith ANDROGEL 1%. The present application excludes the use oftestosterone and uses cyclodextrin as the sole active ingredient. Thisavoids the side effect issues associated with testosterone.

As used herein, the “ophthalmic compositions” are useful for placementonto the surface of an eye of a human or animal. Such compositions arepreferably administered into an eye of a patient in a fluid form. Byadministering the compositions as a fluid, the administration may occurwithout forming an incision in the eye. As used herein, the “transdermalcompositions” deliver a therapeutically effective amount of activeingredient across the skin of a patient. Transdermal compositionstypically involve a carrier (such as a liquid, gel, or solid matrix, ora pressure sensitive adhesive) into which the active ingredient to bedelivered is incorporated.

As used herein, an “active pharmaceutical ingredient” refers totherapeutic agents or substances used to treat a medical ophthalmicdisease or condition of the eye and/or to otherwise beneficially affecta patient's eye, and “sole active pharmaceutical ingredient” refers tothe one and only therapeutic agent or substance used to treat a medicalophthalmic disease or condition of the eye and/or to otherwisebeneficially affect a patient's eye.

The beta-cyclodextrin derivatives described herein are the sole activepharmaceutical ingredient of the ophthalmic compositions. The ophthalmiccompositions do not include any other active pharmaceutical ingredientsfor treating eye diseases. Specifically, the ophthalmic compositions donot include an androgen with a steroidal chemical structure,testosterone, or precursors of testosterone. The ophthalmic compositionsmay include one or more inactive ingredients selected from the groupconsisting of hydroxypropyl guar, xantham gum, trehalose, sodiumchloride, castor oil, cremophor ELP, Polysorbate 80, HPMC 2910, edetatedisodium, glycerin, and a buffer agent. The ophthalmic compositions maybe a water-based formulation.

As used herein, the term “therapeutically effective amount” is intendedto mean a nontoxic but sufficient concentration or amount of abeta-cyclodextrin derivative, and more specifically, a beta-cyclodextrinderivative selected from the group described above, to provide thedesired therapeutic effects. The amount that is effective will vary fromsubject to subject, depending on the age and general condition of theindividual, the cyclic polysaccharide, and the like. Thus, it is notalways possible to specify an exact effective concentration or amount.However, an appropriate effective amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation. Furthermore, the exact effective amount of abeta-cyclodextrin derivative incorporated into a composition or dosageform of the present invention is not critical, so long as theconcentration is within a range sufficient to permit ready applicationof the solution or formulation so as to deliver an amount ofbeta-cyclodextrin derivative-including compound that is within atherapeutically effective range.

2-Hydroxypropyl-beta-cyclodextrin (2-HP-β-CD) (CAS Number: 128446-35-5)is a modified cyclodextrin derivative, and has the following formula I.2,6-Di-O-methyl-beta-cyclodextrin (also known asheptakis(2,6-di-O-methyl)-beta-cyclodextrin, CAS Number 51166-71-3) is amodified cyclodextrin derivative, and has the following formula II.

In a clinical trial to study a drug for treating pterygium, a surprisingdiscovery was made that the vehicle (2-HP-(3-CD Formulation I) reducedthe symptom of foreign body sensation, pain, redness and in particular,light sensitivity and blurred vision in pterygia patients. Pterygium isa common ocular disorder that causes several ocular symptoms that arealso common in MGD. They are also common in disease such as blepharitisand dry eye disease. The meibomian glands in pterygium area are oftendysfunctional. In this clinical trial, several common ocular symptomsincluding irritation, foreign body sensation, pain, light sensitivityand blurred vision, were assessed using questionnaires to the patients.Surprisingly, overall ocular symptom scores combining the scores ofirritations, foreign body sensation, pain, light sensitivity and blurredvision have significantly reduced during cyclodextrin treatment whencomparing to the prior treatment baseline. In particular, lightsensitivity and blurred vision were significantly improved by thevehicle during the treatment compared to the prior treatment baseline.Even more surprising is that these symptom relief effects maintained fora prolong period of 5 months post vehicle treatment. The vehicle's mainingredient was 10% 2-HP-β-CD (w/w).

Compositions and methods for treating ocular symptoms are disclosed. Themethods include administration of a suitable ocular formulationcontaining 2-Hydroxypropyl beta Cyclodextrin (2-HP-β-CD) to patients inneed thereof. The disclosed methods are used for sustained improvementson the overall symptoms associated with MGD, blepharitis and dry eyedisease.

EXAMPLES

The invention is further described in the following representativeexamples, which do not limit the scope of the claimed invention.

Example 1: 2-HP-β-CD Formulation I

The formulation in this example includes 5%-20% (preferably, 10%)2-HP-β-CD (w/w), 0.10-0.30% (preferably, 0.16%) sodium phosphatemonobasic monohydrate (w/w), 0.20-0.80% (preferably, 0.52%) sodiumchloride (w/w), and water. The formulation has a pH value of 4-9(preferably, 7.4).

Example 2: Application of 2-HP-β-CD Formulation I

A Phase 2a Multicenter, Randomized, Vehicle-Controlled, Dose EscalatingStudy was carried out to evaluate the Safety, Efficacy andPharmacokinetics of Nintedanib Ophthalmic Solution in Patients withPrimary or Recurrent Pterygium. 2-HP-β-CD Formulation I was used asvehicle.

The multicenter, randomized, double-masked, vehicle-controlled, parallelstudy was conducted with 28 days three times a day (TID) repeat oculardosing of vehicle and 0.2% nintedanib, followed by 5-month post-dosingobservation.

Results:

In the clinical trial, pterygia patients were asked 15 questions onocular sign, symptom and quality of life. Surprisingly, the 2-HP-β-CDFormulation I caused an unexpected improvement on light sensitivity andblurred vision. Table 1 shows that the two symptoms were statisticallyimproved during treatment at weeks 2 and 4. A trend of effects alsoremained after the stop of treatment at weeks 8, 16, and 24. The resultsare shown in FIG. 1. The other questions didn't generate statisticallysignificant effects.

TABLE 1 Effects of the 2-HP-β-CD Formulation I on sensitivity to lightand blurred vision Day 1 Wk 2 Wk 4 Wk 8 Wk 16 Wk 24 Sensitivity to lightMean veh (n = 23) 0.74 0.26 0.22 0.39 0.45 0.39 SD 1.14 0.45 0.42 0.720.96 0.72 TTEST vs baseline 0.031 0.015 0.148 0.167 0.175 Blurred visionMean veh (n = 23) 1.09 0.57 0.57 0.61 1.00 0.52 SD 1.31 1.20 0.95 1.031.23 0.51 TTEST vs baseline 0.004 0.025 0.086 0.776 0.039

Example 3: 2-HP-β-CD Formulation II

The formulation in this example includes 0.1-05% Castor Oil (w/w),0.1-1.0% Polysorbate 80, super-refined (w/w), 0.1-1.0% Cremophor ELP(w/w), 5-20% 2-HP-β-CD (w/w), 0.010-0.30% Citric Acid (w/w),0.030-0.060% Sodium Citrate (w/w), 0.01-1.0% HPMC 2910 (w/w), 0.01-0.5%Edetate Disodium (w/w), and water. The formulation has a pH value of4.0-9.0. Glycerin is used to adjust the osmolality of the solution to280-300 mOsm/kg.

Example 4: Application of 2-HP-β-CD Formulation II

A Phase 3 Multicenter, Randomized, Vehicle-Controlled, Dose EscalatingStudy will be carried out to evaluate the Safety, Efficacy andPharmacokinetics of Nintedanib Ophthalmic Solution in Patients withPrimary or Recurrent Pterygium. 2-HP-β-CD Formulation II will be used asvehicle.

The treatment time of the Phase 3 trial is longer than that of the Phase2a trial. The results are shown in FIG. 2.

Example 5: Application of 2-HP-β-CD Formulation I

A Phase 2a Multicenter, Randomized, Vehicle-Controlled, Dose EscalatingStudy was carried out to evaluate the Safety, Efficacy andPharmacokinetics of Nintedanib Ophthalmic Solution in Patients withPrimary or Recurrent Pterygium. The multicenter, randomized,double-masked, vehicle-controlled, parallel study was conducted with 28days three times a day (TID) repeat ocular dosing of vehicle and 0.2%nintedanib, followed by 5-month post-dosing observation. 2-HP-β-CDformulation listed in Example 1 was used as the vehicle.

Pterygium patients often have meibomian gland atrophy and clinical signsand symptoms of MGD, including ocular pain, itchy, foreign bodysensation, redness, sensitivity to light and blue vision. In the PhaseII clinical trial, pterygia patients were asked 15 questions on ocularsymptom, vision-related functioning and quality of life via PterygiumSymptom and Life Quality (PSLQ) questionnaires.

Results:

PSLQ analyses were performed for 4 average category scores; Overall,Ocular Symptoms, Vision-Related Functioning, and Quality of Life Impact.Results of the analyses are summarized in Table 2 through Table 5.2-HP-β-CD -treated group showed significant improvements in PSLQ scoreswhen compared to the baseline. Statistically significant changes(improvements) from baseline were detected in the 2-HP-β-CD -treatedgroup at Weeks 2, 4, and 8 for Overall PSLQ scores and at Weeks 2, 4 and8 for Ocular Symptom scores, and at Week 2 for Quality of Life Impactscores and at Weeks 4 and 8 for the Vision-Related Functioning scores.

Surprisingly, the improvements on ocular symptoms and vision-relatedfunctioning were not only observed during 2-HP-β-CD treatment period atWeeks 2 and 4, but also continued after 2-HP-β-CD treatment period atWeek 8.

TABLE 2 PSLQ: Overall Average Score - Baseline and Changes from Baselineat Each Follow-up Visit: Modified Intent-to-Treat Population Timepoint2-HP-β-CD Statistic (N = 23) Baseline Mean (SD)  0.70 (0.66) Change fromBaseline at Week 2 Mean (SD) −0.28 (0.45) p-value [a] 0.007 Change fromBaseline at Week 4 Mean (SD) −0.35 (0.51) p-value [a] 0.004 Change fromBaseline at Week 8 Mean (SD) −0.30 (0.55) p-value [a] 0.016 Change fromBaseline at Week 16 Mean (SD) −0.20 (0.64) p-value [a] 0.164 Change fromBaseline at Week 24 Mean (SD) −0.22 (0.73) p-value [a] 0.158 [a] Withintreatment group change from baseline p-value based on the one samplet-test.

TABLE 3 PSLQ: Average Ocular Symptom Score - Baseline and Changes fromBaseline at Each Follow-up Visit: Modified Intent-to-Treat PopulationTimepoint 2-HP-β-CD Statistic (N = 23) Baseline Mean (SD)  0.88 (0.81)Change from Baseline at Week 2 Mean (SD) −0.36 (0.69) p-value [a] 0.019Change from Baseline at Week 4 Mean (SD) −0.46 (0.71) p-value [a] 0.005Change from Baseline at Week 8 Mean (SD) −0.39 (0.84) p-value [a] 0.035Change from Baseline at Week 16 Mean (SD) −0.29 (0.79) p-value [a] 0.102Change from Baseline at Week 24 Mean (SD) −0.33 (0.90) p-value [a] 0.090[a] Within treatment group change from baseline p-value based on the onesample t-test.

TABLE 4 PSLQ: Average Vision-Related Functioning Score - Baseline andChanges from Baseline at Each Follow-up Visit: Modified Intent-to-TreatPopulation Timepoint 2-HP-β-CD Statistic (N = 23) Baseline Mean (SD)0.57 (0.80) Change from Baseline at Week 2 Mean (SD) −0.27 (0.65)p-value [a] 0.067 Change from Baseline at Week 4 Mean (SD) −0.48 (0.65)p-value [a] 0.003 Change from Baseline at Week 8 Mean (SD) −0.43 (0.62)p-value [a] 0.004 Change from Baseline at Week 16 Mean (SD) −0.23 (0.56)p-value [a] 0.08  Change from Baseline at Week 24 Mean (SD) −0.11 (1.1)p-value [a] 0.617 [a] Within treatment group change from baselinep-value based on the one sample t-test.

TABLE 5 PSLQ: Average Quality of Life Impact Score - Baseline andChanges from Baseline at Each Follow-up Visit: Modified Intent-to-TreatPopulation Timepoint 2-HP-β-CD Statistic (N = 23) Baseline Mean (SD) 0.57 (0.92) Change from Baseline at Week 2 Mean (SD) −0.19 (0.39)p-value [a] 0.029 Change from Baseline at Week 4 Mean (SD) −0.19 (0.50)p-value [a] 0.082 Change from Baseline at Week 8 Mean (SD) −0.17 (0.52)p-value [a] 0.140 Change from Baseline at Week 16 Mean (SD) −0.13 (0.68)p-value [a] 0.392 Change from Baseline at Week 24 Mean (SD) −0.15 (0.59)p-value [a] 0.239 [a] Within treatment group change from baselinep-value based on the one sample t-test.

Further analysis was done to assess the potential therapeutic effect of10% 2-hydroxypropyl beta-cyclodextrin on patients with symptoms ofocular pain, itchy, foreign body sensation, redness, sensitivity tolight and blurred vision. These ocular symptoms are often observed inMGD patients. Scores of these symptoms were graded by patients as partof PSLQ questionnaires.

(1) Dry eye patients vs. Non-dry eye patients (based upon patients'medical history) with the combined nintedanib—treated andvehicle-treated groups. Results: Dry eye patients vs. Non-dry eyepatients on Ocular Symptom Score as part of PSLQ: FIG. 7 shows mean PSLQocular symptom score at each schedule visit for pterygium patients withdry eye or with no dry eye and FIG. 8 shows average change from baselineof ocular symptom score at each schedule visit for pterygium patientswith dry eye or with no dry eye.

The pterygium patients with dry eye condition was compared withpterygium patients with no dry eye condition. In this comparison, allpterygium patients with dry eye condition in the drug and vehicletreated group was combined and the same was done for pterygium patientswith no dry eye condition. Number of data points for each group wereN=17 for dry eye and N=18 for no dry eye. The data showed thatstatistically significant differences at Week 2 (p=0.042) and Week 4(p=0.025) between dry eye group and no dry eye group. The meandifferences in PSLQ ocular symptom reduction were 0.50 at Week 2 and0.61 at Week 4. Pterygium patients with dry eye condition had higherbaseline score and had bigger reduction from baseline of ocular symptomscore during treatment period when compared to pterygium patients withno dry eye condition.

(2) Nintedanib vs. Vehicle for dry eye patients (based upon patients'medical history). Results: Nintedanib vs. Vehicle in Dry eye patients onOcular Symptom Score as part of PSLQ: FIG. 9 shows mean PSLQ ocularsymptom score at each schedule visit for pterygium patients with dry eyeand FIG. 10 shows average change from baseline of ocular symptom scoreat each schedule visit for pterygium patients with dry eye.

Pterygium patients with dry eye condition in the drug treated group andvehicle treated group had similar responses for PSLQ ocular symptom. Thechange from baseline for PSLQ ocular symptom was similar during thetreatment period and no statistically significant differences observedat any timepoints.

In conclusion: the evidences support that 10%2-hydroxypropyl-beta-cyclodextrin had effects on PSLQ responses frompterygium patients with dry eye condition and pterygium patients with nodry eye condition. The magnitude of reduction in PSLQ ocular symptomscore was statistically significant bigger in pterygium patients withdry eye condition than in pterygium patients with no dry eye condition.

On the contrary, when compared pterygium patients with dry eye conditionthat were treated with Nintedanib 0.2% or Vehicle, there was nostatistically significant differences between two treatment groups. Thisindicates Nintedanib 0.2% was not the main cause for the reduction inPSLQ scores in pterygium patients with dry eye condition while 10%2-hydroxypropyl-beta-cyclodextrin was the major factor that causedreduction in PSLQ scores in the pterygium patients with dry eyecondition.

Example 6: Solubility of cholesterol in cyclodextrin

Solubility of cholesterol in the presence of cyclodextrin (CD) has beenmeasured and reported (Nishijo, J., Moriyama, S. and Shiota S., Chem.Pharm. Bull., 51(11) 1253-1257, 2003). Solubility of Cholesterol in thePresence of CD Aliquots (7.0 ml) of CD aqueous solution of theappropriate concentration and excess cholesterol were placed in 20 mlL-type test tubes and the tubes were sealed. The test tubes were kept at10, 25, 37 and 45° C., respectively, with shaking, for 1 week untilsolubility equilibrium was achieved. Then the solution was filteredthrough the membrane and 3.0 ml of color-producing reagent was added to0.1 ml of the filtrate. Then the reaction mixture was heated for 5 minat 37° C. and the absorbance at 600 nm was measured using thecalibration curve made in advance. Stability of cholesterol-CD complexwas determined by a Shimadzu RF-503A fluorescence spectrophotometer at25° C. Table 6 shows the increase in absorbance due to cholesteroldissolved by CDs in aqueous solution at 37° C.

TABLE 6 Increase in Absorbance Due to Cholesterol Dissolved by CDs inAqueous Solution at 37° C. CD [a] Absorbance (600 nm) Without CD 0Alpha-CD 0 Beta-CD 0 Gamma-CD 0 HP-beta-CD 0.01 DOM-beta-CD 0.336 [a]Concentration of CDs added is 1.0 × 10⁻² M.

As shown in Table 6, in the presence of alpha-CD, beta-CD and gamma-CD,the absorbances were zero, suggesting that these CDs do not form solublecomplexes with cholesterol in aqueous solution. While only a slightincrease in absorbance was observed in the presence of HP-beta-CD, aremarkable increase in absorbance was observed in the presence ofDOM-beta-CD. These results suggest that DOM-beta-CD has a strong abilityto form soluble complex with cholesterol in aqueous solution, butHP-beta-CD only a weak ability. Although soluble complex formations ofcholesterol with alpha-CD, beta-CD and gamma-CD were not detected,insoluble complex formation might occur.

Example 7: Safety of 10% HP-β-CD (the vehicle in the Phase 2 clinicaltrial)

This example demonstrated the safety of HP-β-CD in human. The data wasderived from the stage 2 of the Phase 2 clinical trial in pterygiumpatients who were topically administered 10% HP-β-CD as the vehicle ofthe testing article. The patients were treated for 4 weeks withthree-time a day dosing and then followed up for another 20 weeks afterthe stop of treatment. The safety evaluation included the 20 weeks ofnon-treatment period. The example showed the vehicle results and not thetesting article that was not relevant to this application.

All safety analyses were conducted on the safety population. MedDRAnomenclature was used to code adverse events. The number and percent ofpatients reporting adverse events were tabulated based on preferredterms and/or system organ class. Summary tables were generated for alladverse events regardless of causality as well as for treatment-relatedadverse events.

The mean duration of exposure to study treatment was 28 days with 96% ofpatients having a treatment duration of at least 28 days (Table 7).

TABLE 7 Extent of Exposure to Study Treatment Safety Population VehicleExposure (N = 25) Treatment duration (days) Mean 28.0 SD 0.0 Median 28.0Min, Max 28, 28 n 24 Treatment duration, n (%)  >=1 day 24 (96.0) >=14days 24 (96.0) >=28 days 24 (96.0) Missing 1 (4.0)

Adverse Events

A summary of adverse events was presented in Table 8. Oculartreatment-emergent adverse events (TEAEs) of any causality were reportedin the study eyes of 16.0% (4/25) of patients in the Vehicle group.There were no study discontinuations due to AEs. No deaths ordrug-related serious adverse events were reported in the study.

TABLE 8 Summary of Adverse Events Safety Population Vehicle (N = 25) n(%) All Ocular TEAEs Study Eye 4 (16.0) Non-study Eye 0 TreatmentRelated Ocular TEAEs Study Eye 1 (4.0) Non-study Eye 0 All Non-ocularTEAEs 7 (28.0) Treatment Related Non-ocular TEAEs 0 Serious TEAEs 1(4.0) Treatment-related Serious TEAEs 0 Discontinuation due to adverseevents 0 Deaths 0

In summary, 10% HP-β-CD as the vehicle in the Phase 2 pterygium clinicaltrial showed excellent safety profile, with only one treatment-relatedTEAE reported.

Example 8: Screening of various cyclodextrin (CD) and CD derivatives forability to dissolve cholesterol in water

Purpose: To determine the level of cholesterol that can be dissolved inwater when 10 different CDs and their derivatives were added at threeconcentrations.

Methods: CDs tested were: alpha-cyclodextrin (ACD), beta-cyclodextrin(BCD), gamma-cyclodextrin (GCD), 2-hydroxypropyl-alpha-cyclodextrin(HP-ACD), 2-hydroxypropyl-beta-cyclodextrin (HP-BCD),2-hydroxypropyl-gamma-cyclodextrin (HP-GCD), randommethyl-beta-cyclodextrin (M-BCD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-BCD),6-O-alpha-maltosyl-beta-cyclodextrin (6-AM-BCD), and sulfobutylatedbeta-cyclodextrin (SBE-BCD).

All CD solutions were prepared with starting 20% (w/v) solutions byaccurately adding about 800 mg CDs in 4 milliliter water, 1% and 10%were diluted from this 20% solution to 2 mL for each sample preparationexperiment.

Cholesterol was added accurately to all CD water solutions at about 40mg/mL or about 80 mg per 2 mL. This amount of cholesterol was enough tofully saturate the CD solutions with white settlements or floating orboth. All samples were conditioned at ambient by shaking using a rotatorfor 5 days.

After the equilibration with shaking for 5 days at ambient, the clear orsemi-clear portion was filtered with 0.2 μm filter. 50 μL of thefiltered solution was diluted with 450 μL methanol (10 X) for HPLCanalysis. NOVAPAK phenyl column (7.6 cm by 3.9 mm I.D.) was used with amobile phase of acetonitrile: water (70:30) at a flow rate of 0.5 ml/minand detection at UV at 210 nm.

Results are summarized in Table 9.

TABLE 9 Cholesterol-dissolving activities of various CDs CD %Concentrations of Cholesterol in CDs Solution (mg/mL) (w/v) M-BCD DM-BCD6-AM-BCD HP-BCD SBE-BCD BCD HP-GCD GCD HP-ACD ACD 0 0.02 0.02 0.02 0.020.02 0.02 0.02  0.02 0.02 0.02 1 0.15 0.19 0.03 0.01 0.002 ND ND ND NDND 10 6.03 5.13 2.57 0.82 0.03 NA 0.003 ND ND ND 20 14.2 10.43 3.38 2.980.15 NA 0.011 ND ND ND Note: ND = not detectable; NA = not tested.

All the natural unmodified CDs had no or extremely low ability (belowmethod sensitivity) to dissolve cholesterol in water. The HP derivativeshowed unexpected large differences among alpha-, beta-, and gamma-CDs.HP-ACD had no detectable cholesterol dissolving activity and HP-GCD hadextremely low levels, in contrast, HP-BCD had substantial ability todissolve cholesterol.

Further research was focused on the BCD type and other derivatives ofthis type of CD. The results were surprising and unexpected: the abilityof cholesterol dissolving ability was rank ordered as following:methyl->hydroxypropyl->sulfobutyl->unmodified (no activity). Among themethylated BDs, M-BCD and DM-BCD were similar and were the best,6-Am-BCD was about half lower. For the CDs that showedcholesterol-dissolving activity, the CD concentrations were proportionalto the activities.

Surprising Findings Summary:

1) Natural alpha-, beta- and gamma-CDs had no to very low ability todissolve cholesterol in water.

2) For CD derivatives, only beta-CD derivatives showed substantialability to dissolve cholesterol in water.

3) For the beta-CD derivatives, the rank order of ability was:methyl->hydroxypropyl->sulfobutyl-.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the spirit or scope of the invention. Thus, it isintended that the present invention cover the modifications andvariations of this invention provided they come within the scope of theappended claims and their equivalents.

1-10. (canceled)
 11. A steroidal-androgen-free composition comprising abeta-cyclodextrin derivative as an active pharmaceutical ingredient,wherein the steroidal-androgen-free composition is an ophthalmiccomposition.
 12. The steroidal-androgen-free composition of claim 11,wherein the steroidal-androgen-free composition consists essentially ofthe beta-cyclodextrin derivative and one or more ingredients selectedfrom the group consisting of hydroxypropyl guar, xantham gum, trehalose,sodium chloride, castor oil, cremophor ELP, Polysorbate 80, HPMC 2910,edetate disodium, glycerin, a buffer agent, and water.
 13. The method ofclaim 12, wherein the buffer agent is selected from the group consistingof sodium phosphate monobasic monohydrate, citric acid, and sodiumcitrate.
 14. The steroidal-androgen-free composition of claim 11,wherein the beta-cyclodextrin derivative is present in thesteroidal-androgen-free composition at a concentration of 0.1% w/w to30% w/w.
 15. The steroidal-androgen-free composition of claim 11,wherein the beta-cyclodextrin derivative is selected from the groupconsisting of (2-hydroxypropyl)-beta-cyclodextrin,methyl-beta-cyclodextrin, 6-monodeoxy-6-monoazido-beta-cyclodextrin,6-monodeoxy-6-monoiodo-beta-cyclodextrin,6-monodeoxy-6-monothio-beta-cyclodextrin,6-monodeoxy-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monobromo-beta-cyclodextrin,heptakis(2,3,6-tri-O-benzoyl)-beta-cyclodextrin,heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin,heptakis(2,6-di-O-methyl)-beta-cyclodextrin,heptakis(6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-chloro)-beta-cyclodextrin,heptakis(6-deoxy-6-bromo)-beta-cyclodextrin,heptakis(6-deoxy-6-iodo)-beta-cyclodextrin,heptakis(6-deoxy-6-thio)-beta-cyclodextrin, sulfobutylatedbeta-cyclodextrin, acetyl beta-cyclodextrin,carboxymethyl-beta-cyclodextrin, succinyl-beta-cyclodextrin,(2-carboxyethyl)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin,6-monodeoxy-6-monoamino-beta-cyclodextrin,heptakis(6-deoxy-6-amino)-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(2,3,-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoaminoto -beta-cyclodextrin,6-monodeoxy-6-monoamino-random-methyl-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(6-sulfo)-beta-cyclodextrin, heptakis (2,3-di-O-acetyl-6-sulfo)beta cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-beta-cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-beta-cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-(2-carboxyethyl)thio)-beta-cyclodextrin, and acombination thereof.
 16. The steroidal-androgen-free composition ofclaim 11, wherein the steroidal-androgen-free composition is a solution,a suspension, an emulsion, a gel, an ointment, or a cream.
 17. Thesteroidal-androgen-free composition of claim 11, wherein thesteroidal-androgen-free composition is an artificial tear or alubricant.
 18. A steroidal-androgen-free composition consisting of abeta-cyclodextrin derivative, sodium chloride, a buffer agent, andwater.
 19. The steroidal-androgen-free composition of claim 18, whereinthe beta-cyclodextrin derivative is selected from the group consistingof (2-hydroxypropyl)-beta-cyclodextrin, methyl-beta-cyclodextrin,6-monodeoxy-6-monoazido-beta-cyclodextrin,6-monodeoxy-6-monoiodo-beta-cyclodextrin,6-monodeoxy-6-monothio-beta-cyclodextrin,6-monodeoxy-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monoazido-6-mono-O-(p-toluenesulfonyl)-beta-cyclodextrin,6-monodeoxy-6-monobromo-beta-cyclodextrin,heptakis(2,3,6-tri-O-benzoyl)-beta-cyclodextrin,heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin,heptakis(2,6-di-O-methyl)-beta-cyclodextrin,heptakis(6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-chloro)-beta-cyclodextrin,heptakis(6-deoxy-6-bromo)-beta-cyclodextrin,heptakis(6-deoxy-6-iodo)-beta-cyclodextrin,heptakis(6-deoxy-6-thio)-beta-cyclodextrin, sulfobutylatedbeta-cyclodextrin, acetyl beta-cyclodextrin,carboxymethyl-beta-cyclodextrin, succinyl-beta-cyclodextrin,(2-carboxyethyl)-beta-cyclodextrin, sulfobutylated beta-cyclodextrin,6-monodeoxy-6-monoamino-beta-cyclodextrin,heptakis(6-deoxy-6-amino)-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(2,3,-di-O-methyl)-hexakis(6-O-methyl)-6-monodeoxy-6-monoaminoto -beta-cyclodextrin,6-monodeoxy-6-monoamino-random-methyl-beta-cyclodextrin,(2-hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin,heptakis(6-sulfo)-beta-cyclodextrin, heptakis (2,3-di-O-acetyl-6-sulfo)beta cyclodextrin, heptakis(2,3-di-O-methyl-6-sulfo)-beta-cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-amino)-beta-cyclodextrin,heptakis(2,3-di-O-methyl-6-deoxy-6-azido)-beta-cyclodextrin,heptakis(6-deoxy-6-(2-carboxyethyl)thio)-beta-cyclodextrin, and acombination thereof.
 20. The steroidal-androgen-free composition ofclaim 18, wherein the buffer agent is selected from the group consistingof sodium phosphate monobasic monohydrate, citric acid, and sodiumcitrate.
 21. The steroidal-androgen-free composition of claim 18,wherein the steroidal-androgen-free composition consists of 5%-20% ofthe beta-cyclodextrin derivative, 0.20%-0.80% of sodium chloride,0.10-0.30% of sodium phosphate monobasic monohydrate, and water.